The LHX2-OTX2 transcriptional regulatory module controls retinal pigmented epithelium differentiation and underlies genetic risk for age-related macular degeneration

Mazal Cohen-Gulkar, Ahuvit David, Naama Messika-Gold, Mai Eshel, Shai Ovadia, Nitay Zuk-Bar, Maria Idelson, Yamit Cohen-Tayar, Benjamin Reubinoff, Tamar Ziv, Meir Shamay, Ran Elkon*, Ruth Ashery-Padan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Tissue-specific transcription factors (TFs) control the transcriptome through an association with noncoding regulatory regions (cistromes). Identifying the combination of TFs that dictate specific cell fate, their specific cistromes and examining their involvement in complex human traits remain a major challenge. Here, we focus on the retinal pigmented epithelium (RPE), an essential lineage for retinal development and function and the primary tissue affected in age-related macular degeneration (AMD), a leading cause of blindness. By combining mechanistic findings in stem-cell-derived human RPE, in vivo functional studies in mice and global transcriptomic and proteomic analyses, we revealed that the key developmental TFs LHX2 and OTX2 function together in transcriptional module containing LDB1 and SWI/SNF (BAF) to regulate the RPE transcriptome. Importantly, the intersection between the identified LHX2-OTX2 cistrome with published expression quantitative trait loci, ATAC-seq data from human RPE, and AMD genome-wide association study (GWAS) data, followed by functional validation using a reporter assay, revealed a causal genetic variant that affects AMD risk by altering TRPM1 expression in the RPE through modulation of LHX2 transcriptional activity on its promoter. Taken together, the reported cistrome of LHX2 and OTX2, the identified downstream genes and interacting co-factors reveal the RPE transcription module and uncover a causal regulatory risk single-nucleotide polymorphism (SNP) in the multifactorial common blinding disease AMD.

Original languageEnglish
Article numbere3001924
JournalPLoS Biology
Volume21
Issue number1
DOIs
StatePublished - Jan 2023

Funding

FundersFunder number
Cancer Biology Research Center
Claire and Amedee Maratier Institute for the Study of Blindness
Edmond J. Safra Center for Bioinformatics
Israel Ministry of Science3-17557
Tsadok Cohen and Heiner Westphal
Visual Disorders
United States-Israel Binational Science Foundation317652, CA-18116, 2013016
Israel Science Foundation1128/20
Tel Aviv University
Ministry of Health, State of Israel
Sackler Faculty of Medicine, Tel-Aviv University

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